Retinal artery occlusion is an indication that the patient is at risk of vascular occlusion elsewhere in the body and therefore requires prompt investigation following diagnosis in the younger population. Ophthalmologists have the opportunity to gain a unique and direct view of a patient’s vascular state. Although ophthalmologists are generally not involved in managing the systemic cause of a patient’s retinal artery occlusion, it is important for ophthalmologists to know about the aetiology and management of retinal artery occlusions in different age groups in order to correctly refer the patient on for optimal and timely management.
Ophthalmological assessment of retinal damage via retinal photography, visual field testing and often fluorescein angiography is warranted [20]. Further systemic investigations include direct visualization of head and neck vasculature via CT angiography/ MRI and carotid duplex ultrasound, an echocardiogram and ECG to identify arrhythmias and structural heart defects that may promote thrombosis/ emboli [20]. A more extensive array of haematological investigations is required in younger patients (< 50 years) to investigate any cause of a ‘hypercoagulable state’ or autoimmune disorder [20]. These include a thrombophilia (coagulation screen, protein C&S, factor V Leiden, anti-phospholipid, plasminogen activator) [1, 2, 20] and autoimmune/vasculitic screen (ANA, anti-double stranded DNA antibody, ANCA, lupus anticoagulant, anticardiolipin antibody) [2, 20]. Other important blood tests include B12 & folate, TFTs, homocysteine levels, blood film, myeloma screen and syphilis screen [1,2,3].
Homocysteine is a sulfhydryl containing amino acid produced as a result of methionine metabolism (an essential amino acid) (ref. Fig. 4) [6]. The two main metabolic pathways are transsulfuration and remethylation, both of which require vital enzymes and vitamin cofactors to function normally. It is therefore understandable that vitamin deficiency and enzymatic defects can result in defective homocysteine metabolism. Auto-oxidated forms of homocysteine are involved in processes that result in increased cell toxicity namely thrombosis, oxidant stress, apoptosis, endothelial cell damage and vascular smooth muscle proliferation [6, 7]. It is via these mechanisms that hyperhomocysteinaemia has been shown to be an independent risk factor for atherosclerotic vascular disease including myocardial infarction, cerebrovascular events and retinal vascular occlusive disease. This risk is graded, relating to an incremental increase in risk per 5 μmol/L increase in homocysteine concentration [8,9,10,11,12].
Hyperhomocysteinaemia is graded as mild (15–30 μmol/L), moderate/intermediate (30–100 μmol/L) and severe (> 100 μmol/L) based on concentrations measured during fasting [6, 21]. Some studies have revealed that between 5 and 10% of the general population have varying levels of hyperhomocysteinaemia and this may reach as high as 30–40% in the elderly population [4, 5].
Homocysteine levels become elevated due to genetic, nutritional and disease related processes, most often occurring in combination. Genetic mutations encoding enzymes involved in homocysteine metabolism include, most commonly, impaired MTHFR enzyme activity which can raise homocysteine levels by up to 25% [6]. The MTHFR enzyme supports conversion of homocysteine to methionine, a vital link in the homocysteine metabolism pathway [22]. The MTHFR gene is located on chromosome 1 with up to 33 rare mutations associated with severe enzyme deficiencies. The C677T (cytosine to thymine mutation at nucleotide 677) genetic defect is a more common mutation, with the homozygous TT mutation being associated with milder enzymatic deficiency [23, 24]. There have been conflicting reports as to whether this genetic mutation in isolation conveys a raised homocysteine to a level where it causes vascular occlusive disease including retinal artery occlusion specifically [6, 25,26,27,28,29,30,31]. However, a more dramatic rise in homocysteine levels are seen when this genetic defect occurs in combination with vitamin deficiency [9, 21, 31].
Cystathionine-β-synthase (CBS) mutations result in severely raised homocystiene levels and there are in excess of 100 different types of mutation for this enzyme. The 1278 T subtype is implicated in the rare inherited inborn error of metabolism, homocystinuria [6]. Other clinical features of homocystinuria include mental retardation, skeletal abnormalities, ectopia lentis and congenital glaucoma.
Given that a number of vitamins are important cofactors for homocysteine metabolism, their deficiency can result in accumulation of homocysteine. These dietary vitamins include folate, vitamin B6, and vitamin B12. Even borderline levels of folate deficiency have been associated with raised homocysteine [4]. Folic acid provides a substrate for tetrahydrofolate (THF) within the folate cycle, allowing normal methionine synthase (MS) activity to occur [6]. Vitamin B12 is a vital cofactor in normal MS activity and vitamin B6 is a key factor in normal CBS activity [6].
Chronic disease, namely renal failure, diabetes mellitus, hypothyroidism and severe psoriasis and drugs including anticonvulsants, methotrexate, caffeine, tobacco and alcohol can also contribute to raised homocysteine levels [6, 32].
It makes sense that introducing interventions to lower plasma homocysteine via vitamin replacement should reduce the risk of further vascular occlusive disease and studies have shown that vitamin replacement effectively lowers homocysteine levels [13]. However, meta-analysis of randomized controlled trials looking at homocysteine lowering interventions have failed to associate the use of vitamin replacement with a reduction in major vascular related events [13]. One study specific to young subjects aged between 18 and 40 years revealed that, although the use of B12, folic acid and B6 vitamin replacement reduced the level of homocysteine, it did not cause an improvement in endothelial dependant vasodilatation or antithrombotic function [7].
Also, despite the fact that the relationship between hyperhomocysteinaemia and retinal vascular occlusion has been increasingly reported [14,15,16,17,18,19], research is yet to be carried out into whether reducing homocysteine levels results in a reduction in the risk of further retinal vascular occlusion [12, 14].
